16-728534-C-G

Variant names:

• chr16-728534-C-G
• rs374833821
• NM_032304.4:c.428C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032304.4(HAGHL):​c.428C>G​(p.Ser143Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000654 in 1,376,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0690
• Publications: 0 publications found

Genes affected

HAGHL (HGNC:14177): (hydroxyacylglutathione hydrolase like) Predicted to enable hydroxyacylglutathione hydrolase activity and metal ion binding activity. Predicted to be involved in methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2438623).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032304.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGHL	NM_032304.4	MANE Select	c.428C>G	p.Ser143Trp	missense	Exon 5 of 8	NP_115680.1	Q6PII5-2
	HAGHL	NM_001323636.2		c.428C>G	p.Ser143Trp	missense	Exon 6 of 8	NP_001310565.1
	HAGHL	NM_207112.2		c.428C>G	p.Ser143Trp	missense	Exon 6 of 7	NP_996995.1	Q6PII5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGHL	ENST00000389703.8	TSL:1 MANE Select	c.428C>G	p.Ser143Trp	missense	Exon 5 of 8	ENSP00000374353.3	Q6PII5-2
	HAGHL	ENST00000389701.9	TSL:1	n.615C>G		non_coding_transcript_exon	Exon 4 of 7
	HAGHL	ENST00000341413.8	TSL:2	c.428C>G	p.Ser143Trp	missense	Exon 6 of 7	ENSP00000341952.4	Q6PII5-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000654 AC: 9 AN: 1376760 Hom.: 0 Cov.: 32 AF XY: 0.00000294 AC XY: 2 AN XY: 679204

African (AFR) AF: 0.00 AC: 0 AN: 31234

American (AMR) AF: 0.00 AC: 0 AN: 34974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24590

East Asian (EAS) AF: 0.00 AC: 0 AN: 35514

South Asian (SAS) AF: 0.00 AC: 0 AN: 78258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4192

European-Non Finnish (NFE) AF: 0.00000836 AC: 9 AN: 1076032

Other (OTH) AF: 0.00 AC: 0 AN: 57434

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.63	N
PhyloP100		-0.069
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.020	D
Polyphen		0.023	B
Vest4		0.34
MutPred		0.63		Loss of disorder (P = 0.0036)
MVP		0.29
MPC		0.27
ClinPred		0.068	T
GERP RS		-8.5
Varity_R		0.042
gMVP		0.40
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374833821; hg19: chr16-778534;